Cancer is a disease of abnormal cell growth often leading to death. Cancer is treated by three principal means; surgical removal of the tumor, therapeutic radiation, and treatment with anti-tumor chemical compounds. Treatment with chemical compounds, termed chemotherapy, is often hindered by the inherent toxicity of the chemicals to the patient and resistance of the tumor to the chemical treatment. Therefore the identification of less toxic anti-tumor agents capable of inhibiting growth of resistant tumors and/or treating cancer is of great importance. Alternative mechanism and targets for anti-tumor/anti-cancer therapy represent viable potential means of obtaining these goals.
Protein prenylation is an important lipid post-translational modification that affects about 0.5% of cellular proteins.1 Prenylated proteins are covalently modified with either farnesyl or geranylgeranyl isoprenoid via thioether bonds to the C-terminal cysteine residues. Prenylated proteins mainly belong to the low molecular weight GTPase family, such as the Ras oncoproteins, and depend heavily on prenylation for their proper cellular localization and biological function.
Over the past decade, the major effort in designing prenyltransferase inhibitors focused on protein farnesyltransferase (FTase), with the goal of specifically blocking malignant transformation caused by mutated Ras proteins. A particular emphasis was placed on developing highly selective FTase inhibitors (FTIs) to avoid potential toxicity. The approach has been very successful, even though, the antitumor activity of FTIs likely results from blocking farnesylation of one or more target-proteins other than Ras.2,3 Some FTIs have demonstrated significant antitumor activity and lack of toxicity in animal models, and several compounds are currently in phase II clinical trials.
Recently, protein geranylgeranyltransferase I (GGTase-1) has gained increasing attention because many of its substrates, such as RhoC, RhoA, Rac-1, Cdc42, R-Ras, TC-21 were found to play critical roles in promoting tumorigenesis and/or metastasis.4-8 In addition, K-Ras, the highly mutated and the most relevant target for Ras-targeted anticancer drug discovery, was found to be activated through geranylgeranylation when its farnesylation is inhibited by FTIs.2-3 Further reasons for targeting GGTase-I in the development of novel anticancer agents arise from the desirable biological activities observed for GGTase inhibitors (GGTIs). These agents inhibited human tumor growth in vitro and in vivo with a mechanism that is consistent with a cell cycle arrest at the G1 phase.9-11 This includes induction of the CDK inhibitor p21 waf, inhibition of CDK2 and CDK4 kinase activities and induction of hypophosphorylation of pR.9-11 No significant toxicity was observed in animal studies at the doses tested.
The complex networks of signal transduction pathways involving key GGTases have not been fully characterized. Therefore, developing highly selective GGTIs, would provide valuable tools to study the related proteins in normal and cancer cell growth. Specific GGTase-I inhibitors, in combination with other anti-cancer therapy, may have significant potential as cancer chemotherapeutic agents for the treatment of malignant tumors advanced to the metastatic stage.